Neal Futran

Cisplatin and Radiotherapy With or Without Erlotinib in Locally Advanced Squamous Cell Carcinoma of the Head and Neck: A Randomized Phase II Trial

PURPOSE The combination of cisplatin and radiotherapy is a standard treatment for patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN). Cetuximab-radiotherapy is superior to radiotherapy alone in this population, validating epidermal growth factor receptor (EGFR) as a target. Erlotinib is a small-molecule inhibitor of EGFR. Adding EGFR inhibition to standard cisplatin-radiotherapy may improve efficacy. PATIENTS AND METHODS Patients with locally advanced SCCHN were randomly assigned to receive cisplatin 100 mg/m(2) on days 1, 22, and 43 combined with 70 Gy of radiotherapy (arm A) or the same chemoradiotherapy with erlotinib 150 mg per day, starting 1 week before radiotherapy and continued to its completion (arm B). The primary end point was complete response rate (CRR), evaluated by central review. The secondary end point was progression-free survival (PFS). Available tumors were tested for p16 and EGFR by fluorescent in situ hybridization. RESULTS Between December 2006 and October 2011, 204 patients were randomly assigned. Arms were well balanced for all patient characteristics including p16, with the exception of more women on arm A. Patients on arm B had more rash, but treatment arms did not differ regarding rates of other grade 3 or 4 toxicities. Arm A had a CRR of 40% and arm B had a CRR of 52% (P = .08) when evaluated by central review. With a median follow-up time of 26 months and 54 progression events, there was no difference in PFS (hazard ratio, 0.9; P = .71). CONCLUSION Erlotinib did not increase the toxicity of cisplatin and radiotherapy in patients with locally advanced HNSCC but failed to significantly increase CRR or PFS.

Quality of life after laryngectomy: Are functional disabilities important?

The purpose of this study was to determine the functional disabilities and overall quality of life (QOL) of patients successfully treated (ie, without evidence of disease at two years) for laryngeal or hypopharyngeal cancer by a total laryngectomy.

The indications and outcomes in the use of osteocutaneous radial forearm free flap

Whether secondary to cancer surgery ablation or trauma, surgeons are faced with defects of the mandible or maxilla that would be best reconstructed with a thin, pliable soft tissue component and vascularized bone. A subset of these challenging wounds do not require the bicortical bone necessary to reestablish structural integrity or to retain a dental prosthesis, because the soft tissue needs are more critical than the bony needs. It is this niche that the radial forearm osteofaciocutaneous free flap (RFOFF) fulfills well. In the past, potential and real donor site morbidity has precluded the routine use of this flap. New methods to reduce this morbidity have rekindled our use of this flap.

Genomewide Gene Expression Profiles of HPV-Positive and HPV-Negative Oropharyngeal Cancer: Potential Implications for Treatment Choices

OBJECTIVE To study the difference in gene expression between human papillomavirus (HPV)-positive and HPV-negative oral cavity and oropharyngeal squamous cell carcinoma (OSCC). DESIGN We used Affymetrix U133 plus 2.0 arrays to examine gene expression profiles of OSCC and normal oral tissue. The HPV DNA was detected using polymerase chain reaction followed by the Roche LINEAR ARRAY HPV Genotyping Test, and the differentially expressed genes were analyzed to examine their potential biological roles using the Ingenuity Pathway Analysis Software, version 5.0. SETTING Three medical centers affiliated with the University of Washington. PATIENTS A total of 119 patients with primary OSCC and 35 patients without cancer, all of whom were treated at the setting institutions, provided tissues samples for the study. RESULTS Human papillomavirus DNA was found in 41 of 119 tumors (34.5%) and 2 of 35 normal tissue samples (5.7%); 39 of the 43 HPV specimens were HPV-16. A higher prevalence of HPV DNA was found in oropharyngeal cancer (23 of 31) than in oral cavity cancer (18 of 88). We found no significant difference in gene expression between HPV-positive and HPV-negative oral cavity cancer but found 446 probe sets (347 known genes) differentially expressed in HPV-positive oropharyngeal cancer than in HPV-negative oropharyngeal cancer. The most prominent functions of these genes are DNA replication, DNA repair, and cell cycling. Some genes differentially expressed between HPV-positive and HPV-negative oropharyngeal cancer (eg, TYMS, STMN1, CCND1, and RBBP4) are involved in chemotherapy or radiation sensitivity. CONCLUSION These results suggest that differences in the biology of HPV-positive and HPV-negative oropharyngeal cancer may have implications for the management of patients with these different tumors.

A multicenter phase II study of tgDCC-E1A for the intratumoral treatment of patients with recurrent head and neck squamous cell carcinoma.

The anti‐cancer gene, E1A, can be complexed to a lipid carrier, DC‐Cholesterol:DOPE, to form tgDCC‐E1A, which can be injected directly into tumors.

Examination of Oral Cancer Biomarkers by Tissue Microarray Analysis

OBJECTIVE To validate the DNA microarray results on a subset of genes that could potentially serve as biomarkers of oral squamous cell carcinoma (OSCC) by examining their expression with an alternate quantitative method and by assessing their protein levels. DESIGN Based on DNA microarray data from our laboratory and data reported in the literature, we identified 6 potential biomarkers of OSCC to investigate further. We used quantitative real-time polymerase chain reaction to examine expression changes of CDH11, MMP3, SPARC, POSTN, TNC, and TGM3 in OSCC and histologically normal control tissues. We further examined validated markers at the protein level by immunohistochemical analysis of OSCC tissue microarray sections. RESULTS Quantitative real-time polymerase chain reaction analysis revealed upregulation of CDH11, SPARC, POSTN, and TNC gene expression and decreased TGM3 expression in OSCC tissue compared with control tissue; MMP3 was not found to be differentially expressed. In tissue microarray immunohistochemical analyses, SPARC (secreted protein, acidic, rich in cysteine), periostin, and tenascin C exhibited increased protein expression in tumor tissue compared with control tissue, and their expression was primarily localized within tumor-associated stroma rather than tumor epithelium. Conversely, transglutaminase 3 protein expression was found only within keratinocytes in control tissue and was significantly downregulated in cancer cells. CONCLUSIONS Of 6 potential gene markers of OSCC, initially identified by DNA microarray analyses, differential expression of CDH11, SPARC, POSTN, TNC, and TGM3 were validated by quantitative real-time polymerase chain reaction. Differential expression and localization of proteins encoded by SPARC, POSTN, TNC, and TGM3 were clearly shown by tissue microarray immunohistochemical analysis.

Comparison of Approaches for Oral Cavity Cancer Resection: Lip Split versus Visor Flap

OBJECTIVE: To compare lip-split and visor flap approaches to the oral cavity in terms of morbidity, margins, and locoregional recurrence. DESIGN AND SETTING: Retrospective case series at the University of Washington, Seattle. METHODS: Seventy patients undergoing resection of advanced (T4) anterior oral cavity squamous cell carcinoma requiring fibula reconstruction were grouped according to surgical access procedure performed (lip-split [LS] or visor flap [VF]). Data on surgical morbidity, margin status, and outcomes were compared. RESULTS: Recurrence rates and positive margins were similar for both groups. Rates of postoperative fistulae were 6.8% (LS) vs 0% (VF) and for oral incompetence 14.6% (LS) vs 6.9% (VF). Most of the fistulas (37.5%) were in irradiated patients. Neither group had any malunions. CONCLUSIONS: There is no significant difference in pathological margins or rates of local recurrence when using either the lip-split or the visor approach. The lip-split approach has a higher rate of postoperative fistula formation than the visor flap approach; fistula formation may be associated with previous irradiation.

A 13-gene signature prognostic of HPV-negative OSCC: discovery and external validation.

Purpose: To identify a prognostic gene signature for patients with human papilloma virus (HPV)–negative oral squamous cell carcinomas (OSCC). Experimental Design: Two gene expression datasets were used: a training dataset from the Fred Hutchinson Cancer Research Center (FHCRC, Seattle, WA; n = 97) and a validation dataset from the MD Anderson Cancer Center (MDACC, Houston, TX; n = 71). We applied L1/L2-penalized Cox regression models to the FHCRC data on the 131-gene signature previously identified to be prognostic in patients with OSCCs to identify a prognostic model specific for patients with high-risk HPV-negative OSCCs. The models were tested with the MDACC dataset using a receiver operating characteristic (ROC) analysis. Results: A 13-gene model was identified as the best predictor of HPV-negative OSCC-specific survival in the training dataset. The risk score for each patient in the validation dataset was calculated from this model and dichotomized at the median. The estimated 2-year mortality (±SE) of patients with high-risk scores was 47.1% (±9.24%) compared with 6.35% (±4.42) for patients with low-risk scores. ROC analyses showed that the areas under the curve for the age, gender, and treatment modality-adjusted models with risk score [0.78; 95% confidence interval (CI), 0.74–0.86] and risk score plus tumor stage (0.79; 95% CI, 0.75–0.87) were substantially higher than for the model with tumor stage (0.54; 95% CI, 0.48–0.62). Conclusions: We identified and validated a 13-gene signature that is considerably better than tumor stage in predicting survival of patients with HPV-negative OSCCs. Further evaluation of this gene signature as a prognostic marker in other populations of patients with HPV-negative OSCC is warranted. Clin Cancer Res; 19(5); 1197–203. ©2012 AACR.

A 13-gene signature prognostic of HPV-negative oral cavity cancer: discovery and external validation

Purpose: To identify a prognostic gene signature for patients with human papilloma virus (HPV)–negative oral squamous cell carcinomas (OSCC). Experimental Design: Two gene expression datasets were used: a training dataset from the Fred Hutchinson Cancer Research Center (FHCRC, Seattle, WA; n = 97) and a validation dataset from the MD Anderson Cancer Center (MDACC, Houston, TX; n = 71). We applied L1/L2-penalized Cox regression models to the FHCRC data on the 131-gene signature previously identified to be prognostic in patients with OSCCs to identify a prognostic model specific for patients with high-risk HPV-negative OSCCs. The models were tested with the MDACC dataset using a receiver operating characteristic (ROC) analysis. Results: A 13-gene model was identified as the best predictor of HPV-negative OSCC-specific survival in the training dataset. The risk score for each patient in the validation dataset was calculated from this model and dichotomized at the median. The estimated 2-year mortality (±SE) of patients with high-risk scores was 47.1% (±9.24%) compared with 6.35% (±4.42) for patients with low-risk scores. ROC analyses showed that the areas under the curve for the age, gender, and treatment modality-adjusted models with risk score [0.78; 95% confidence interval (CI), 0.74–0.86] and risk score plus tumor stage (0.79; 95% CI, 0.75–0.87) were substantially higher than for the model with tumor stage (0.54; 95% CI, 0.48–0.62). Conclusions: We identified and validated a 13-gene signature that is considerably better than tumor stage in predicting survival of patients with HPV-negative OSCCs. Further evaluation of this gene signature as a prognostic marker in other populations of patients with HPV-negative OSCC is warranted. Clin Cancer Res; 19(5); 1197–203. ©2012 AACR.

CLINICAL UTILITY OF SOMATOSTATIN RECEPTOR SCINTIGRAPHIC IMAGING (OCTREOSCAN) IN ESTHESIONEUROBLASTOMA: A CASE STUDY AND SURVEY OF SOMATOSTATIN RECEPTOR SUBTYPE EXPRESSION

For tumors that express somatostatin receptors (SSTR), radiolabeled somatostatin analogs, such as 111In‐pentetreotide, can demonstrate the presence of tumor by radioligand uptake using somatostatin receptor scintigraphy (SRS). The use of 111In‐pentetreotide for SRS depends on the specific high affinity of octreotide for SSTR subtypes 2, 3, and 5. Of these, SSTR2 has the greatest affinity for octreotide and the greatest relevance for tumor detection with Octreoscan imaging. Discriminating between postoperative changes and residual or recurrent tumor after extensive skull base surgery is often difficult, but in a case of recurrent esthesioneuroblastoma (ENB) we found the use of Octreoscan imaging clinically useful. To better define the general relevance of this imaging technique in this setting, we analyzed SSTR subtype expression in a panel of ENB tumors.